1. Field of the Invention PA1 (1) ##STR2## wherein Sac is a mono-, di- or trisaccharide, preferably a disaccharide, more preferably cellobiose, maltose or gentiobiose, most preferably lactose; PA1 (2) ##STR3## or a pharmaceutically acceptable cationic or anionic salt thereof, wherein n is three (polyornithine) or four (polylysine), r is an integer from 3 to 200, preferably from 140 to 160, and the chroman is attached to L by the replacement of a hydrogen on a side chain nitrogen; and PA1 (3) [--NH(CH.sub.2).sub.p NH--].sub.q --D wherein p is an integer from 2 to 12, preferably 6, D is a functionalized dextran of molecular weight from 1250 to 30000, preferably from 1250 to 10000, most preferably about 9400, and q is an integer from 1 to 12, L the value of which is not less than m and is in the range from 1.times.10.sup.-4 to 7.times.10.sup.-4 times the average molecular weight of D. PA1 (1) oxidizing dextran of average molecular weight 9400 with about 0.5 equivalents of sodium periodate; PA1 (2) condensing the oxidized dextran at a concentration of 0.5% in aqueous buffer with about 10 equivalents of 1,6-hexanediamine at pH 7.2; PA1 (3) reducing the dextran-hexanediamine Schiff base with about 10 equivalents of sodium borohydride at pH 9.0; and (4) coupling the aminohexylaminodextran with about 1 equivalent of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid in the presence of 2 equivalents of 1-(3-dimethylamino)-3-ethylcarbodiimide at pH 5.5 to 6.5.
The present invention relates to novel amide conjugates of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid with derivatized monosaccharides, oligosaccharides, polysaccharides and with polylysine and polyornithine. The invention also relates to compositions containing these conjugates and the use of the conjugates for the prevention and treatment of reperfusion injury.
2. Information Disclosure Statement
U.S Pat. No. 4,877,810 to Mickle and Wu discloses the use of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (also known as Trolox-C and hereinafter sometimes referred to as TX) for the treatment of cardiac reperfusion injury. Mickle et al. [Ann. Thor. Surg. 553-557 (1989)] also discloses the use of TX for the treatment of reperfusion injury in cardiac tissue.
Taylor et. al [Journal of the American Oil Chemical Society, 622-626 (1981)] describe amides of TX with naturally occurring .alpha.-aminoacids. Specifically disclosed are TX-methionine, TX-tryptophan, TX-histidine and TX-cysteine. The antioxidant activity of the compounds is described in linoleate emulsions and in edible oils such as corn oil.
Schachtet. al. [J. Controlled Release 1, 33-46 (1984)] describe the oxidation of dextran (molecular weight 43,000) with periodate, the condensation of the resulting polyaldehyde with N-(.omega.- aminoalkanoyl)-procainamides and the reduction of the condensation products with sodium cyanoborohydride to provide conjugates of dextran linked to procainamide. The general chemistry of dextran as a drug carrier has been reviewed by Molteni [Methods in Enzymology 112, 285-298 (1985)].
Arnold [Methods in Enzymology 112, 270-285 (1985)] describes conjugates of antineoplastic agents with polylysine. Specifically disclosed are conjugates of methotrexate, anthracyclin and 6-aminonicotinamide with polylysine of Mw 13000, 35000, and 70000.
U.S. Pat. No. 4,401,661 to Schaub et al. discloses N,N'-bis[4-[4-O -(.alpha.-D-glucopyranosyl)-.beta.-D-glucopyranosyloxy]-phenyl]butanediami de as an intermediate in the synthesis of sulfonated diamine complement modulators.